Anxiety disorders are some of the most common emotional disorders, cause considerable morbidity, and represent a significant economic burden. At least three key influences appear to be involved in the etiology of anxiety disorders: a) constitutive genetic differences, b) adverse early life event-mediated epigenetic changes, and c) chronic stress-induced plasticity. Our hypothesis for the present proposal will focus on two types of severe anxiety disorders, panic disorder (PD) and social anxiety disorder (SAD). We propose to study two components of the 'serotonergic dorsal raphe nucleus (DRN)-extended amygdala anxiety network': 1) the DRN-basolateral amygdala (BLA) and 2) the DRN-bed nucleus of the stria terminalis (BNST) pathways, which may be critical components in the pathophysiology of PD and SAD, respectively. We will systematically elucidate the behavioral, cellular and molecular effects of a) repeated stress neurotransmitter corticotropin- releasing factor (CRF)-induced plasticity, and b) two forms of genetic vulnerability, specifically, variations in serotonin transporter (SERT) expression using SERT and rats, and locally silencing the 5HT1A receptor gene in the BLA and BNST in the pathophysiology of PD and SAD in the current proposal. Our future studies will address the three-way interactions of stress plasticity and genetic vulnerability with early life stress (maternal separation)-induced epigenetic effects. In SPECIFIC AIM I, we will test the role of repeated stress- induced long-term plasticity in the BLA-DRN circuit in PD. In SPECIFIC AIM II, the role of long-term plasticity in the BNST-DRN circuit and SAD will be studied. SPECIFIC AIM III will determine the effects of reduced expression of SERT and vulnerability to stress-induced plasticity, whereas SPECIFIC AIM IV will study the role of reduced 5HT1A receptor gene expression in the vulnerability to stress-induced plasticity and pathophysiology of PD and SAD. Thus, the work proposed in this competitive renewal will a) characterize 'stress'and 'gene'interaction models of human anxiety disorders such as PD and SAD, b) study the putative disruption in the 'anxiety'circuitry of the BLA and BNST involved in the transition from adaptive panic and social responses to pathological states, and c) elucidate the molecular changes within the BLA and BNST that occur in anxiety disorders. The results of this project could help develop novel genetically targeted treatments and prevention strategies for disabling illnesses such as PD and SAD. PUBLIC HEALTH RELEVANCE This work will a) study the genetic and molecular mechanisms in the 'anxiety'circuitry in the brain that results in the pathological anxiety states such as panic disorder and social anxiety disorder, and b) characterize stress neuropeptide corticotropin-releasing factor-induced long-term changes and known abnormal serotonin gene interaction models of human panic and social anxiety disorders. The results of these studies could position us to develop novel genetically-targeted treatments and prevention strategies for chronic disabling illnesses such as panic and social anxiety disorder.